Rheumatoid arthritis is a chronic inflammatory disease characterized by inflammation and proliferation of synovial cells; and causes osteoporosis and bone erosion around in the joints, unlike osteoarthritis. Typically, rheumatoid arthritis is progressed in the following steps: inflammation in the synovial membrane spreads to joint capsules, ligaments, tendons, etc (step 1); progressive destruction of joint cartilage leads to narrowing the joint space and destroying tension of both joint capsule and ligament (step 2); inflammation infiltrates into bone, thereby inducing partial bone erosion (step 3); and functional disability is caused in the joint (step 4).
The treatment of rheumatoid arthritis used in the prior arts includes the use of therapeutic agents, for example non-steroidal anti-inflammatory drugs (NSAIDs) such as traditional NSAIDs, salicylates, COX-2 inhibitors, etc; steroids such as prednisolone, triamcinolone, etc; disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, etc; biological agents such as etanercept, infliximab, adalimumab, etc. Typically, NSAIDs and steroids are clinically used in the early stage; and DMARDs are also used according to symptoms and disease activity. In severe cases, biological agents or combination therapy are used in the clinics.
However, the use of biological agents causes very higher medical cost in comparison with the use of other therapeutic agents, which makes it difficult to apply to the patients in the conventional medical practice. NSAIDs involving relatively low medical cost are known as one of the representative drugs to induce side effects in the gastrointestinal tract. It is well-known that the major side effect of DMARDs such as methotrexate and sulfasalazine is also disorders in the gastrointestinal tract (i.e., gastrointestinal disorders). Therefore, when these drugs are applied to a patient suffering from rheumatoid arthritis, a cytoprotective agent (e.g., rebamipide, etc) or a H2-receptor antagonist (e.g., cimetidine, ranitidine, etc) is also co-administered. Gastrointestinal disorders are caused when offensive factors (e.g., gastric acid) are strengthened or defense factors are weakened. Both proton pump inhibitors (e.g., omeprazole) and acid pump antagonists (e.g., revaprazan) are compounds inhibiting the secretion of the offensive factor, i.e., the gastric acid; and cytoprotective agents (e.g., sucralfate, rebamipide) are compounds potentiating defensive factors.